chr15-90803693-C-A

Variant names:

• chr15-90803693-C-A
• rs2227934
• NM_000057.4:c.3531C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000057.4(BLM):​c.3531C>A​(p.Ala1177Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,558 control chromosomes in the GnomAD database, including 23,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1177A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1904 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21859 hom.)
• Consequence: BLM NM_000057.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.00
• Publications: 30 publications found

Genes affected

BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]

BLM Gene-Disease associations (from GenCC):

• Bloom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Genomics England PanelApp, ClinGen, Laboratory for Molecular Medicine
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ENSG00000300894 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 15-90803693-C-A is Benign according to our data. Variant chr15-90803693-C-A is described in ClinVar as Benign. ClinVar VariationId is 92395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000057.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	NM_000057.4	MANE Select	c.3531C>A	p.Ala1177Ala	synonymous	Exon 18 of 22	NP_000048.1	P54132
	BLM	NM_001287246.2		c.3531C>A	p.Ala1177Ala	synonymous	Exon 19 of 23	NP_001274175.1	P54132
	BLM	NM_001287248.2		c.2406C>A	p.Ala802Ala	synonymous	Exon 18 of 22	NP_001274177.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.3531C>A	p.Ala1177Ala	synonymous	Exon 18 of 22	ENSP00000347232.3	P54132
	BLM	ENST00000560509.5	TSL:1	c.3358+5356C>A		intron	N/A	ENSP00000454158.1	H0YNU5
	BLM	ENST00000559724.5	TSL:1	n.*2455C>A		non_coding_transcript_exon	Exon 18 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23353 AN: 151944 Hom.: 1907 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.151 AC: 38074 AN: 251328 AF XY: 0.150

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.0884

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.170 AC: 248242 AN: 1461496 Hom.: 21859 Cov.: 33 AF XY: 0.168 AC XY: 122051 AN XY: 727062

African (AFR) AF: 0.117 AC: 3902 AN: 33470

American (AMR) AF: 0.0935 AC: 4180 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 4318 AN: 26122

East Asian (EAS) AF: 0.177 AC: 7015 AN: 39680

South Asian (SAS) AF: 0.0891 AC: 7683 AN: 86250

European-Finnish (FIN) AF: 0.147 AC: 7830 AN: 53408

Middle Eastern (MID) AF: 0.138 AC: 798 AN: 5768

European-Non Finnish (NFE) AF: 0.182 AC: 202656 AN: 1111698

Other (OTH) AF: 0.163 AC: 9860 AN: 60380

GnomAD4 genome AF: 0.154 AC: 23361 AN: 152062 Hom.: 1904 Cov.: 32 AF XY: 0.150 AC XY: 11157 AN XY: 74322

African (AFR) AF: 0.121 AC: 5004 AN: 41494

American (AMR) AF: 0.111 AC: 1691 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 595 AN: 3470

East Asian (EAS) AF: 0.179 AC: 927 AN: 5178

South Asian (SAS) AF: 0.0934 AC: 450 AN: 4818

European-Finnish (FIN) AF: 0.146 AC: 1537 AN: 10548

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12708 AN: 67972

Other (OTH) AF: 0.149 AC: 315 AN: 2112

Alfa AF: 0.170 Hom.: 3610

Bravo AF: 0.149

Asia WGS AF: 0.136 AC: 474 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Bloom syndrome (6)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	BLM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.0
DANN	Benign	0.50
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2227934; hg19: chr15-91346923; COSMIC: COSV61922667;